48 research outputs found

    Methylation-mediated silencing of PTPRD induces pulmonary hypertension by promoting pulmonary arterial smooth muscle cell migration via the PDGFRB/PLCγ1 axis

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    OBJECTIVE: Pulmonary hypertension is a lethal disease characterized by pulmonary vascular remodeling and is mediated by abnormal proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Platelet-derived growth factor BB (PDGF-BB) is the most potent mitogen for PASMCs and is involved in vascular remodeling in pulmonary hypertension development. Therefore, the objective of our study is to identify novel mechanisms underlying vascular remodeling in pulmonary hypertension. METHODS: We explored the effects and mechanisms of PTPRD downregulation in PASMCs and PTPRD knockdown rats in pulmonary hypertension induced by hypoxia. RESULTS: We demonstrated that PTPRD is dramatically downregulated in PDGF-BB-treated PASMCs, pulmonary arteries from pulmonary hypertension rats, and blood and pulmonary arteries from lung specimens of patients with hypoxic pulmonary arterial hypertension (HPAH) and idiopathic PAH (iPAH). Subsequently, we found that PTPRD was downregulated by promoter methylation via DNMT1. Moreover, we found that PTPRD knockdown altered cell morphology and migration in PASMCs via modulating focal adhesion and cell cytoskeleton. We have demonstrated that the increase in cell migration is mediated by the PDGFRB/PLCγ1 pathway. Furthermore, under hypoxic condition, we observed significant pulmonary arterial remodeling and exacerbation of pulmonary hypertension in heterozygous PTPRD knock-out rats compared with the wild-type group. We also demonstrated that HET group treated with chronic hypoxia have higher expression and activity of PLCγ1 in the pulmonary arteries compared with wild-type group. CONCLUSION: We propose that PTPRD likely plays an important role in the process of pulmonary vascular remodeling and development of pulmonary hypertension in vivo

    G2019S LRRK2 Increases Stress Susceptibility Through Inhibition of DAF-16 Nuclear Translocation in a 14-3-3 Associated-Manner in Caenorhabditis elegans

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    Mutations in leucine-rich repeat kinase 2 (LRRK2) are common causes of familial Parkinson’s disease (PD). Oxidative stress plays a key role in the pathogenesis of PD. Mutations in LRRK2 have been shown to increase susceptibility to oxidative stress. To explore mechanisms underlying susceptibility to oxidative stress in LRRK2 mutants, we generated stable Caenorhabditis elegans (C. elegans) strains in which human LRRK2 proteins including wild type LRRK2 (WT), G2019S LRRK2 (G2019S), and G2019S-D1994A kinase-dead LRRK2 (KD) were expressed in all neurons. Human 14-3-3 β was injected into LRRK2 transgenic worms to allow co-expression of 14-3-3 β and LRRK2 proteins. We found that G2019S transgenic worms had increased sensitivity to stress (heat and juglone treatment) and impaired stress-induced nuclear translocation of DAF-16. In addition, G2019S inhibited ftt2 (a 14-3-3 gene homolog in C. elegans) knockdown-associated nuclear translocation of DAF-16. Comparably, overexpression of human 14-3-3 β could attenuate G2019S-associated toxicity in response to stress and rescued G2019S-mediated inhibition of sod-3 and dod-3 expression. Taken together, our study provides evidence suggesting that 14-3-3-associated inhibition of DAF-16 nuclear translocation could be a mechanism for G2019S LRRK2-induced oxidative stress and cellular toxicity. Our findings may give a hint that the potential of 14-3-3 proteins as neuroprotective targets in PD patients carrying LRRK2 mutations

    Clinical application of superselective transarterial embolization of renal tumors in zero ischaemia robotic-assisted laparoscopic partial nephrectomy

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    ObjectiveTo assess the feasibility and safety of zero ischaemia robotic-assisted laparoscopic partial nephrectomy (RALPN) after preoperative superselective transarterial embolization (STE) of T1 renal cancer.MethodsWe retrospectively analyzed the data of 32 patients who underwent zero ischaemia RALPN after STE and 140 patients who received standard robot-assisted laparoscopic partial nephrectomy (S-RALPN). In addition, we selected 35 patients treated with off-clamp RALPN (O-RALPN) from September 2017 to March 2022 for comparison. STE was performed by the same interventional practitioner, and zero ischaemia laparoscopic partial nephrectomy (LPN) was carried out by experienced surgeon 1-12 hours after STE. The intraoperative data and postoperative complications were recorded. The postoperative renal function, routine urine test, urinary Computed Tomography (CT), and preoperative and postoperative glomerular filtration rate (GFR) data were analyzed.ResultsAll operations were completed successfully. There were no cases of conversion to opening and no deaths. The renal arterial trunk was not blocked. No blood transfusions were needed. The mean operation time was 91.5 ± 34.28 minutes. The mean blood loss was 58.59 ± 54.11 ml. No recurrence or metastasis occurred.ConclusionFor patients with renal tumors, STE of renal tumors in zero ischaemia RALPN can preserve more renal function, and it provides a safe and feasible surgical method

    Shear strength of compacted soils

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    The aim of this Final Year Project is to study the shear strength of soil which are either statically compacted or dynamically compacted and to compare any differences arising from each compaction method. Dynamically compacted soil samples were compacted following the instruction of Modified Proctor Test. For statically compacted soil samples, a California Bearing Ratio (CBR) machine was utilised to compact the soil samples to the same dry density as on the modified Proctor compaction curve. The obtained data were subsequently analysed to investigate the impact of different compaction method to the soil properties.Bachelor of Engineering (Civil

    Heterogeneity of clinical features, EEG and brain imaging findings in anti-leucine-rich glioma-inactivated protein 1 autoimmune encephalitis: a retrospective case series study and review of the literature

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    Abstract Background Anti-leucine-rich glioma-inactivated 1 (LGI-1) autoimmune encephalitis (AE), characterized by rapid decline of memory, seizures, and neuropsychiatric abnormalities, is a rare but devastating disorder. Early diagnosis and treatment are essential to prevent long-term sequelae. In this report, we provide a detailed description of clinical characteristics, laboratory test results, imaging, and electroencephalography (EEG) findings, as well as treatment responses of eight patients with anti-LGI-1 AE treated at our center. Case presentation At the onset, all eight patients presented with confusion/memory deterioration, seizures (including faciobrachial dystonic seizures or other types of seizure), and behavioral changes such as hallucination, paranoia, and anxiety. Four patients were found with severe hyponatremia. Anti-LGI1 antibodies were detected in the cerebrospinal fluid and/or serum of all patients. For patients with faciobrachial dystonic seizures, no discernible scalp EEG change was detected, while EEG recording of patients experiencing other types of seizure showed focal slowing, focal epileptiform discharges, and focal onset seizures. All patients showed abnormal brain magnetic resonance imaging signals, mainly involving the mesial temporal lobe and the hippocampus. In addition, one patient also experienced fulminant cerebral edema during the acute phase of the illness. All patients received immunotherapy and anti-seizure medications and achieved good seizure control. Nevertheless, these patients continued to experience cognitive impairment during their long-term follow-ups. Conclusions The care of anti-LGI1 AE patients requires rapid evaluation, prompt initiation of immunotherapy, and long-term follow-up. The long-term presence of neurocognitive complications observed in these patients underline the importance of developing reliable biomarkers that can distinguish between different subtypes of this disease with heterogeneous clinico-electrographico-radiological features. Further research is needed to understand the molecular mechanisms underlying the heterogeneity, in order to facilitate development of more effective treatments for anti-LGI1 AE

    Study on Copula-based Coordination of Urban Drainage system and Sewage system Design

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    The urban drainage system is co-regulated by various governmental departments, who adopt different standards in designing the system, an attempt not conducive to the prevention of water logging. This study took Zhongshan and Zhuhai as the subjects, proposed the Copula-based design of a drainage system, and calculated the most practical solution to drainage, waterlogging and rainfall based on Kendall’s Return Period, providing references for construction of such projects

    The Value of Hydrologic Information in Reservoir Outflow Decision-Making

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    The controlled outflows from a reservoir are highly dependent on the decisions made by the reservoir operators who mainly rely on available hydrologic information, such as past outflows, reservoir water level and forecasted inflows. In this study, Random Forests (RF) algorithm is used to build reservoir outflow simulation model to evaluate the value of hydrologic information. The Three Gorges Reservoir (TGR) in China is selected as a case study. As input variables of the model, the classic hydrologic information is divided into past, current and future information. Several different simulation models are established based on the combinations of these three groups of information. The influences and value of hydrologic information on reservoir outflow decision-making are evaluated from two different perspectives, the one is the simulation result of different models and the other is the importance ranking of the input variables in RF algorithm. Simulation results demonstrate that the proposed model is able to reasonably simulate outflow decisions of TGR. It is shown that past outflow is the most important information and the forecasted inflows are more important in the flood season than in the non-flood season for reservoir operation decision-making

    Design Combination Optimized Approach for Urban Stormwater and Drainage Systems Using Copula-Based Method

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    Waterlogging disasters cause huge loss of life and property damage every year. In this research, a Copula-based optimization method is proposed to solve the problems in bivariate design of urban stormwater and drainage systems resulting from ignorance of precipitation temporal dependence and discrepancy between different design codes. Optimized design combinations of stormwater and drainage systems conditioned on given Kendall bivariate return periods or return periods of either system can be obtained using the optimization method for the case study of Zhongshan and Zhuhai. Results show that the temporal dependencies between precipitation series with different durations should be carefully considered, which can be sufficiently described by Copula functions. Based on the optimized design combinations, it is found that the planned return periods of stormwater systems in Sponge City Plans are underestimated for both Zhongshan and Zhuhai, which restricts the full use of the drainage systems. According to the optimized results, the planned return periods of stormwater systems in Zhongshan (Zhuhai) should be adjusted to 8.04 a (6.76 a) for the downtown area and 6.52 a (5.59 a) for other areas, conditioned on the planned return periods for P24 h in Sponge City Plans. The proposed optimization method provides a useful approach for the bivariate design of stormwater and drainage systems. The results of this research can give stakeholders references in compiling engineering plans for urban waterlogging prevention and help better balance the conflicts between waterlogging safety and economic efficiency

    Design Combination Optimized Approach for Urban Stormwater and Drainage Systems Using Copula-Based Method

    No full text
    Waterlogging disasters cause huge loss of life and property damage every year. In this research, a Copula-based optimization method is proposed to solve the problems in bivariate design of urban stormwater and drainage systems resulting from ignorance of precipitation temporal dependence and discrepancy between different design codes. Optimized design combinations of stormwater and drainage systems conditioned on given Kendall bivariate return periods or return periods of either system can be obtained using the optimization method for the case study of Zhongshan and Zhuhai. Results show that the temporal dependencies between precipitation series with different durations should be carefully considered, which can be sufficiently described by Copula functions. Based on the optimized design combinations, it is found that the planned return periods of stormwater systems in Sponge City Plans are underestimated for both Zhongshan and Zhuhai, which restricts the full use of the drainage systems. According to the optimized results, the planned return periods of stormwater systems in Zhongshan (Zhuhai) should be adjusted to 8.04 a (6.76 a) for the downtown area and 6.52 a (5.59 a) for other areas, conditioned on the planned return periods for P24 h in Sponge City Plans. The proposed optimization method provides a useful approach for the bivariate design of stormwater and drainage systems. The results of this research can give stakeholders references in compiling engineering plans for urban waterlogging prevention and help better balance the conflicts between waterlogging safety and economic efficiency
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